Candidate: Dr. Bertolatus is a well-trained clinical nephrologist who intends to pursue an academic career in the broad area of renal immunopathology, with specific emphasis on the immunopathogenesis of altered glomerular permselectivity. He has successfully completed studies of renal function and fractional protein clearance in the hexadimethrine (HDM) model of polycation-induced proteinuria. Research: Renal injury in immunologically mediated glomerulonephritis generally leads to proteinuria. Inflammatory cells (neutrophils and monocytes) are the best established mediators of injury, but they are not prominent in most chronic glomerulonephritides. The HDM model establishes that neutralization of glomerular basement membrane (GBM) anions can alter glomerular permselectivity. I plan to examine the hypothesis that immune mechanisms can cause proteinuria by an "HDM-like" interaction with GBM anions. First, I plan to perform specific enzyme digestion studies on isolated GBM to determine the GBM component to which HDM binds. Second, since certain antibodies (noncomplement-fixing anti-GBM antibodies and framents of anti-Fx1A antibodies) can cause proteinuria without complement or inflammatory cells, I plan to perform in vitro and in vivo competitive binding experiments between these antibodies and HDM to determine if both mediate proteinuria by binding to the same site. Finally, because complement can cause proteinuria without participation of inflammatory cells, I plan to test several likely candidates from the complement system (C3a, C5a, C5b-C6 and the membrane attack complex) for their ability to bind to GBM and cause proteinuria. Evidence for neutralization of GBM anions will be sought by competitive binding experiments. These studies should lead to a better undertanding of the mechanism(s) of proteinuria in immunologic renal disease. Environment: The proposed sponsor, Dr. Hunsicker, is an established investigator in the field of renal immunology. The candidate will be a member of a renal division with strong research programs in several areas, including renal physiology, hypertension, transport physiology, and transplantation immunobiology. In addition, there is a strong interdiscipinary Immunology Group and training program. In particular the candidate will have important consultant support from Dr. J. Weiler in complement immunochemistry and from Dr. G. F. DiBona in renal physiology.